21Mitocondri come depositi di calcio Local ER–mitochondria interactions. A representation is depicted of ER–mitochondria relationships and of some of the proteins involved in the cross-talk between the organelles. Ca2+ released from the ER through Ins(1,4,5)P3Rs is taken up by mitochondria through the MCU. Within mitochondria, Ca2+ modulates mitochondrial dehydrogenase activity and thus ATP production. Moreover, mitochondrial Ca2+ uptake regulates the spatio-temporal pattern of the cytosolic Ca2+ signal and, therefore, many Ca2+-dependent cellular processes. Massive and/or a prolonged accumulation of Ca2 in the mitochondria can lead to the opening of the PTP in the IMM and swelling of the organelle or, acting on mitochondria-shaping proteins [DRP-1, hFis1, OPA1, mitofusins (MFNs)], tomitochondrial cristae remodeling and modulation of apoptosis. The ‘in concert’ action of the two organelles in cell death is further supported by the presence on both the ER membrane and the OMM of different components of the Blc-2 family that have either a pro- (BIK, BAX, BAK) or an anti-apoptotic role (Bcl-2, Bcl-XL). ER and mitochondria could be linked physically at specific sites by cytoplasmic molecules (grp75, PACS-2), either directly or through proteins expressed on the two membranes (IP3R, VDAC). Readers are referred to the text for further details. CsmtDHs, Ca2+ sensitive mitochondrial dehydrogenases; Cyt c, cytochrome c; IMM, inner mitochondrial membrane; IP3R, inositol 1,4,5-trisphosphate receptor; OMM, outer mitochondrial membrane; MCU, mitochondrial Ca2+ uniporter; PTP, permeability transition pore; SERCA, sarcoplasmic-endoplasmic reticulum Ca2+ ATPase; VDAC, voltage-dependent anion channel.